RAS: Target for Cancer Therapy

Saxena, Nandita; Lahiri, Sitanshu S.; Hambarde, Shashank; Tripathi, R. P.

doi:10.1080/07357900802087275

Cited by 69 publications

(63 citation statements)

References 52 publications

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“…We found that colorectal cancer cell lines were also highly susceptible to IGFBP7-mediated apoptosis, consistent with the high frequency of activating BRAF or RAS mutations, and presumably increased BRAF-MEK-ERK signaling, in colorectal cancers (1,9). Significantly, previous studies have found that IGFBP7 expression is lost in human colorectal cancers (17,18), consistent with the possibility that IGFBP7 is a colorectal cancer tumor suppressor (19,20).…”

Section: Discussionsupporting

confidence: 68%

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Efficacy of IGFBP7 for treatment of metastatic melanoma and other cancers in mouse models and human cell lines

Wajapeyee

Kapoor

Mahalingam

et al. 2009

Molecular Cancer Therapeutics

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We recently identified the secreted protein IGFBP7 as a factor required for an activated BRAF oncogene to induce senescence or apoptosis in primary human cells. In human melanomas containing an activating BRAF mutation (BRAF-positive melanomas), IGFBP7 is epigenetically silenced, which seems to be a critical step in melanoma genesis. Restoration of IGFBP7 function by the addition of recombinant IGFBP7 (rIGFBP7) induces apoptosis in BRAF-positive human melanoma cell lines, and systemically administered rIGFBP7 markedly suppresses the growth of BRAF-positive primary tumors in xenografted mice. Here we further evaluate the role of IGFBP7 in the treatment of BRAF-positive melanoma and other malignancies. We find that in human metastatic melanoma samples IGFBP7 is epigenetically silenced and at an even higher frequency than that found in primary melanomas. Using a murine experimental metastasis assay, we show that systemic administration of rIGFBP7 markedly suppresses the growth of metastatic disease and prolongs survival. An analysis of the NCI60 panel of human cancer cell lines reveals that in addition to melanoma, IGFBP7 induces apoptosis in several other cancer types, in particular colorectal cancer cell lines. In general, IGFBP7 induces apoptosis in human cancer cell lines that have an activating mutation in BRAF or RAS, and that are sensitive to chemical inhibition of BRAF-MEK-ERK signaling. Significantly, systemically administered rIGFBP7 blocks the growth of colorectal tumors containing an activating RAS or BRAF mutation in mouse xenografts. The results presented here, in conjunction with those from previous studies, justify the further development of IGFBP7 as an anticancer agent.

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Section: Discussionsupporting

confidence: 68%

“…In addition, up to 30% of solid tumors contain activating RAS mutations, which can also increase BRAF-MEK-ERK signaling (reviewed in ref. 9). We therefore investigated the potential use of IGFBP7 in the treatment of other cancers.…”

Section: Susceptibility Of Nci60 Human Cancer Cell Lines To Igfbp7 Trmentioning

confidence: 99%

Efficacy of IGFBP7 for treatment of metastatic melanoma and other cancers in mouse models and human cell lines

Wajapeyee

Kapoor

Mahalingam

et al. 2009

Molecular Cancer Therapeutics

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“…A total of 3 × 10 6 A549, H460, HCT116, or MDAMB231 cells were injected s.c. into the flank region of 6-wk-old female athymic mice (Janvier). When tumors reached 50 mm 3 , the mice were randomized into four groups (n = 7/group) for the following treatment: vehicle, RAF265 (12 mg/kg daily), RAD001 (12 mg/kg daily), or both. All drug were administered over 14 d (6 d on, 2 d off, 6 d on), and the drug combination was administered concurrently.…”

Section: In Vivo Experimentsmentioning

confidence: 99%

“…Different pharmacologic strategies have been developed to inhibit KRAS oncogenic activation, including inhibition of its association with the plasma membrane (prenylation and postprenylation inhibitors), downstream signaling (kinase inhibitor), upstream pathways (kinase inhibitor and monoclonal antibody), and protein expression of RAS or other components of the pathway (small interfering RNA and antisense oligonucleotides; ref. 3). However, several of these therapeutic agents have yielded disappointing results (4).…”

Section: Introductionmentioning

confidence: 99%

Dependence on Phosphoinositide 3-Kinase and RAS-RAF Pathways Drive the Activity of RAF265, a Novel RAF/VEGFR2 Inhibitor, and RAD001 (Everolimus) in Combination

Mordant

Loriot

Leteur

et al. 2010

Molecular Cancer Therapeutics

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Activation of phosphatidylinositol-3-kinase (PI3K)-AKT and Kirsten rat sarcoma viral oncogene homologue (KRAS) can induce cellular immortalization, proliferation, and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy. This study assessed the consequences of inhibiting these two pathways in tumor cells with activation of KRAS, PI3K-AKT, or both. We investigated whether the combination of a novel RAF/vascular endothelial growth factor receptor inhibitor, RAF265, with a mammalian target of rapamycin (mTOR) inhibitor, RAD001 (everolimus), could lead to enhanced antitumoral effects in vitro and in vivo. To address this question, we used cell lines with different status regarding KRAS, PIK3CA, and BRAF mutations, using immunoblotting to evaluate the inhibitors, and MTT and clonogenic assays for effects on cell viability and proliferation. Subcutaneous xenografts were used to assess the activity of the combination in vivo. RAD001 inhibited mTOR downstream signaling in all cell lines, whereas RAF265 inhibited RAF downstream signaling only in BRAF mutant cells. In vitro, addition of RAF265 to RAD001 led to decreased AKT, S6, and Eukaryotic translation initiation factor 4E binding protein 1 phosphorylation in HCT116 cells. In vitro and in vivo, RAD001 addition enhanced the antitumoral effect of RAF265 in HCT116 and H460 cells (both KRAS mut, PIK3CA mut); in contrast, the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells. The combination of RAF and mTOR inhibitors is effective for enhancing antitumoral effects in cells with deregulation of both RAS-RAF and PI3K, possibly through the cross-inhibition of 4E binding protein 1 and S6 protein. Mol Cancer Ther; 9(2); 358-68. ©2010 AACR.

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“…In this regard, identification of genes or molecular pathways that are responsible for the development and progression of breast cancer with understanding of their clinical significance are necessary, and may aid in the development of novel approaches for the effective treatment and prognostic prediction of breast cancer. Towards this end, our study focused on Ras GTPase-activating protein 1 (RASA1), which functions to inactivate Ras-GTPase and inhibit mitogenic signaling to downstream protein partners through its N-terminal SH2-SH3-SH2 domains (4)(5)(6). Aberrant expression of RASA1 protein occurs in ~30% of all human cancers, including breast cancer, but in up to 90% of pancreatic cancers (7).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of Ras GTPase-activating protein 1 is associated with poor survival of breast invasive ductal carcinoma patients

Liu

Sun

et al. 2014

Oncology Reports

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Abstract. Ras GTPase-activating protein 1 (RASA1) functions to inactivate Ras-GTPase and inhibit the mitogenic signal. Reduction or loss of RASA1 expression occurs during human cancer development and progression. This study investigated RASA1 expression in normal and breast cancer tissue specimens to determine the association with prognosis of breast cancer patients. Two sets of patient samples (45 fresh tissues and 373 paraffin-embedded tissues) were analyzed for RASA1 expression using RT-qPCR and immunohistochemistry. The results showed that the expression of RASA1 mRNA was lower in breast cancer tissues than in the corresponding normal tissues (P<0.001). Additionally, RASA1 expression was reduced in 60.6% (226/373) of breast cancer tissues. The reduced RASA1 expression was significantly associated with tumor lymph node metastasis (P=0.002), advanced TNM stages (P=0.017), estrogen receptor (ER) expression (P=0.002), Ki-67 (P=0.009), higher histological grade (P<0.001), and triple-negative breast cancer (P=0.041). Moreover, the reduced RASA1 expression was associated with shorter disease-free survival (P=0.036) and overall survival (P<0.001) of breast cancer patients. RASA1 expression, together with tumor lymph-node metastasis, TNM stage, Her-2 expression, and triple-negative breast cancer were independent factors in predicting survival of breast cancer patients. In conclusion, RASA1 expression is frequently reduced in breast cancer tissues, and the reduced RASA1 expression is associated with breast cancer progression and poor survival and disease-free survival of patients.

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RAS: Target for Cancer Therapy

Cited by 69 publications

References 52 publications

Efficacy of IGFBP7 for treatment of metastatic melanoma and other cancers in mouse models and human cell lines

Efficacy of IGFBP7 for treatment of metastatic melanoma and other cancers in mouse models and human cell lines

Dependence on Phosphoinositide 3-Kinase and RAS-RAF Pathways Drive the Activity of RAF265, a Novel RAF/VEGFR2 Inhibitor, and RAD001 (Everolimus) in Combination

Downregulation of Ras GTPase-activating protein 1 is associated with poor survival of breast invasive ductal carcinoma patients

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